Background on new treatments for alzheimer's disease

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New treatments for Alzheimer's disease around corner

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Sirtuin proteins

Sirtuin proteins

What's a sirtuin protein? Perhaps this will jog your memory. Not quite two months ago I wrote about resveratrol – the trace ingredient in red wine that may (or may not) have longevity-extending effects. See the article for plenty of details, but there are a few summary points to repeat here.

First, resveratrol may not occur in sufficiently high concentrations in red wine to offer practical health benefits to humans. Second, there are other compounds in red wine (and red or purple grape skins) which may play a larger role than resveratrol in the reported health benefits of red wine. Third, it is suspected that some of the health benefits observed in experiments with mice fed diets having high concentrations of resveratrol may be a result of its activation of a gene that produces the enzyme called SIRT1, which is a "sirtuin" protein. But, fourth, the observed health benefits of resveratrol may also be due to other effects. In summary, that situation with red wine and resveratrol is still not very clear.

However, it's specifically the sirtuin protein SIRT1 (and some closely related variants) we're interested in here, for reasons we'll get to in a moment. But to set the stage a little further, SIRT1 itself (and related proteins) has been of interest to biologists for over ten years because SIRT1 and its relatives appear to affect the longevity (usually in a positive way) of individuals belonging to several diverse eukaryotic species, ranging from yeast and nematodes to mammals. And this effect seems to be closely related to the observed beneficial effects on longevity of calorie restriction – effects that have been observed for many decades.

There's a little history behind the name of the protein SIRT1. It begins with certain proteins, which were observed in yeast, and which seemed to have something to do with the longevity of yeast cells. There were several of these proteins, which were called Silent Information Regulators. Three of them, in particular, known as SIR2, SIR3, and SIR4, seemed to be implicated in the longevity effect, although they are not structurally similar. Ultimately SIR2 proved to be the most important, and remarkably, a gene in the nematode Caenorhabditis elegans turned out not only to be a close analogue of SIR2 but also to have similar longevity-enhancing effects.

Because of their interesting effects, such proteins became known as "sirtuins" (get it?). It turns out that there are at least seven similar human proteins, named SIRT1 through SIRT7. Of these, it is SIRT1 that has (for good reason) attracted the most attention. It is an enzyme, in particular a histone deacetylase enzyme. Such enzymes are able to efficiently silence the expression of a variety of genes, so they are involved in a wide diversity of biological processes, as I've written about before. (And as I hope to write much more about.)

There are all sorts of interesting things to note about the human sirtuins, but the most notable recent finding, which is very relevant to calorie restriction and was announced at almost the same time as my resveratrol post, is this:

Eat Less To Live Longer: Calorie Restriction Linked To Long Healthy Lives (9/26/07)

Now, reporting in the September 21 issue of the journal Cell, researchers from Harvard Medical School, in collaboration with scientists from Cornell Medical School and the National Institutes of Health, have discovered two genes in mammalian cells that act as gatekeepers for cellular longevity. When cells experience certain kinds of stress, such as caloric restriction, these genes rev up and help protect cells from diseases of aging.

"We've reason to believe now that these two genes may be potential drug targets for diseases associated with aging," says David Sinclair, associate professor of pathology at Harvard Medical School and senior author on the paper.

The new genes that Sinclair's group have discovered, in collaboration with Anthony Sauve of Cornell Medical School and Rafael de Cabo of NIH, are called SIRT3 and SIRT4. They are members of a larger class of genes called sirtuins. (Another gene belonging to this family, SIRT1, was shown last year to also have a powerful impact on longevity when stimulated by the red-wine molecule resveratrol.)

David Sinclair, of course, has been heavily involved in research on SIRT1 and resveratrol, as discussed here. He is also co-founder of Sirtris Pharmaceuticals, which is investigating drugs that target sirtuins. Sinclair is a former student of Leonard Guarente, who is also very prominent in sirtuin research, and who had a great deal to do with investigation of the analogous proteins in yeast and nematodes.

One of the most interesting things about the longevity-enhancing effects of sirtuin proteins in yeast and nematodes is that they seem to achieve their effects by rather different means. In yeast, one cause of aging is the formation of "ribosomal DNA circles", and SIR2 (under appropriate conditions) can inhibit this. In C. elegans, on the other hand, the biological effect that retards aging is the inhibition of "insulin signaling". So what is it that SIRT3 and SIRT4 do in the cells of humans (and other mammals)?

In this paper, the newly discovered role of SIRT3 and SIRT4 drives home something scientists have suspected for a long time: mitochondria are vital for sustaining the health and longevity of a cell.

Mitochondria, a kind of cellular organ that lives in the cytoplasm, are often considered to be the cell's battery packs. When mitochondria stability starts to wane, energy is drained out of the cell, and its days are numbered. In this paper, Sinclair and his collaborators discovered that SIRT3 and SIRT4 play a vital role in a longevity network that maintains the vitality of mitochondria and keeps cells healthy when they would otherwise die.

When cells undergo caloric restriction, signals sent in through the membrane activate a gene called NAMPT. As levels of NAMPT ramp up, a small molecule called NAD begins to amass in the mitochondria. This, in turn, causes the activity of enzymes created by the SIRT3 and SIRT4 genes--enzymes that live in the mitochondria--to increase as well. As a result, the mitochondria grow stronger, energy-output increases, and the cell's aging process slows down significantly.

Other news stories on this research:

Researchers Pinpoint Link Between Caloric Restriction and Longevity

When under stress, two genes within mitochondria guard against cell death

By Jeffrey Perkel

Posted 9/20/07

THURSDAY, Sept. 20 (HealthDay News) -- Harvard researchers report they have uncovered a molecular clue that seems to explain why cutting calories might lengthen your life.

It turns out that mitochondria guard against cell death, and two specific genes within the mitochondria actually carry out that task, the scientists say. Mitochondria are compartments within a cell that are dedicated to energy production, and their loss is thought to be a major cause of aging.

The research also identifies two potential drug targets that could be exploited to slow down the aging process, said lead researcher David Sinclair, director of the Paul F. Glenn Laboratories for Aging Research at Harvard Medical School.

Sinclair and his colleagues found that, when either rat or human cells were deprived of nutrients (as in a caloric-restriction diet), the overall cellular concentration of a compound known as NAD dropped precipitously -- but not within mitochondria. Indeed, following any kind of cellular stress, mitochondrial NAD concentration actually increased.

Sinclair's team found that mitochondria can synthesize their own NAD to withstand stress, thereby helping the cells stay alive long enough to repair themselves.

Two members of a family of genes called sirtuins were required for this effect to occur, the authors found. Those proteins, SIRT3 and SIRT4, both reside within the mitochondria, and they need NAD to do their jobs.

"We were able to mimic calorie restriction in a dish," said Sinclair, "and that's important, because for decades, people knew calorie restriction made the cells less prone to death, but not how it worked, and we tracked it down to the mitochondria and to SIRT3 and SIRT4."

The findings were published in the Sept. 21 issue of Cell.

"This is really a great paper, and it basically provides very new knowledge about how NAD biosynthesis is regulated in our cells," said Dr. Shin-ichiro Imai, an assistant professor of molecular biology and pharmacology at the Washington University School of Medicine, in St. Louis.

The mammalian sirtuin family contains seven members, one of which, SIRT1, had previously been implicated in mammalian aging. "What we publish now is there are two more [sirtuins] that could lead to important drugs," Sinclair said.

"What's exciting is these genes make proteins that reside in mitochondria, and we discovered that if those genes keep mitochondria active, that's the gatekeeper of cell health," he added. "The cell can be essentially dead, but if the mitochondria and the sirtuins are active, the cells will live."

This suggests that if SIRT3 and SIRT4 could be chemically activated, it might be possible to achieve the benefits of caloric restriction without the diet. That could slow the progress of diseases based on cell death, such as Alzheimer's, cancer and diabetes, he said, and possibly extend life span as a result.

Sinclair said he is now looking for compounds that could activate SIRT3, and, as co-founder of Sirtris Pharmaceuticals, a drug development company that focuses on sirtuins, he is in a position to do so.

Imai was guarded on the question of whether pharmacologic activation of sirtuins is necessarily a good idea -- cell death is nature's way of eliminating severely damaged, and potentially cancerous, cells, after all.

"In general, there are benefits to increasing cell survival, but still we don't know precise details to this decision-making process," he explained. "So, I am very cautious about this. However, scientifically, I think this discovery is great, because it gives hope to us to develop a drug via the sirtuins."

Sirtris already has one sirtuin-activating compound in clinical trials. The company recently announced it was initiating early clinical trials of SRT501, a SIRT1 activator based on resveratrol, a compound found in red wine.

"This paper indicates that several other sirtuins, SIRT3 and SIRT4, also play an important role in sensing the energy environment and linking calorie restriction to beneficial effects on health," said Sirtris Chief Executive Officer Christoph Westphal.

"We have continued to develop new drugs to target SIRT1, but we also think SIRT3 and SIRT4 are going to be very promising drug targets," he added.

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Aging handout week 1

Aging is any change in an organism over time. Aging refers to a multidimensional process of physical, psychological, and social change (Hultsch and Deutsch). Some dimensions of aging grow and expand over time, while others decline. Reaction time, for example, may slow with age, while knowledge of world events and wisdom may expand (Schaie). Research shows that even late in life potential exists for physical, mental, and social growth and development. Aging is an important part of all human societies reflecting the biological changes that occur, but also reflecting cultural and societal conventions. Age is usually measured in full years — and months for young children. A person's birthday is often an important event.

The term "aging" is somewhat ambiguous. Stuart-Hamilton (1994) notes how distinctions may be made between "universal aging" (age changes that all people share) and "probabilistic aging" (age changes that may happen to some, but not all people as they grow older, such as the onset of Type Two diabetes). Chronological aging, referring to how old a person is, is arguably the most straightforward definition of aging and may be distinguished from "social aging" (society's expectations of how people should act as they grow older) and "biological aging" (an organism's physical state as it ages). Stuart-Hamilton also notes distinction between "proximal aging" (age-based effects that come about because of factors in the recent past) and "distal aging" (age-based differences that can be traced back to a cause early in person's life, such as childhood poliomyelitis).

Population aging is the increase in the number and proportion of older people in society. Population aging has three possible causes: migration, longer life expectancy (decreased death rate), and decreased birth rate. The societal effects of age are great. Young people tend to commit most crimes, they are more likely to push for political and social change, to develop and adopt new technologies, and to need education. Older people have different requirements from society and government as opposed to young people, and frequently differing values as well. Older people are also far more likely to vote, and in many countries the young are forbidden from voting, and thus the aged have comparatively more political influence.

[edit] Senescence

Main article: Senescence

In biology, senescence is the state or process of aging. Cellular senescence is a phenomenon where isolated cells demonstrate a limited ability to divide in culture (the "Hayflick Limit," discovered by Leonard Hayflick in 1965), while Organismal senescence is the aging of organisms.
A map showing median age figures for 2001
A map showing median age figures for 2001

Aging is not an unavoidable property of life. Instead, it is the result of a genetic program coded in genes. Numerous species show no sign of aging, the best known being perennial plants (e.g. trees) which can live thousands of years and be multiplied by cuttings without limit. Many amphibians and large fish also seem to be free of aging. In these species, adults constantly reproduce only to destroy their youngs, usually by eating them. Therefore, "immortal" species evolve more slowly than species that age.

Aging is believed to be favoured by natural selection because it accelerates the evolution rate of a species by increasing the number of generations per unit of time. By dying away, the old individuals liberate the resources for their offsprings, thus increasing their chance at survival. Essentially, aging is therefore the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory).

Organismal aging is generally characterized by the declining ability to respond to stress, increasing homeostatic imbalance and increased risk of disease. Because of this, death is the ultimate consequence of aging.

Some researchers are treating aging as a "disease" in gerontology (specifically biogerontologists). That is, as genes that have an effect on aging are discovered, aging is increasingly being regarded in a similar fashion to other genetic conditions; potentially "treatable." As an example of genes known to affect the aging process, the sirtuin family of genes have been shown to have a significant effect on the lifespan of yeast and nematodes. Numerous other examples exist of genes that affect lifespan including RAS1 and RAS2 (yeast genes, although a human homologue exists). Over-expression of RAS2 increases lifespan in yeast substantially.

In addition to genetic ties to lifespan, diet has been shown to substantially affect lifespan in many animals. Specifically, caloric restriction (that is, restricting calories to 30-50% less than an ad libitum animal would consume, while still maintaining proper nutrient intake), has been shown to increase lifespan in mice up to 50%. Caloric restriction works on many other species beyond mice (including species as diverse as yeast and Drosophila), and appears (though the data is not conclusive) to increase lifespan in primates according to a study done on Rhesus monkeys at the National Institute of Health (US).


Drug companies are currently searching for ways to mimic the lifespan-extending effects of caloric restriction without having to severely reduce food consumption, and with respect to cellular senescence, it has been shown that individual cells can be immortalized by the introduction of an additional gene for telomerase.

[edit] Dividing the lifespan

A human life is often divided into various ages. Because biological changes are slow moving and vary from person to person, arbitrary dates are usually set to mark periods of human life. In some cultures the divisions given below are quite varied.

In the USA, adulthood legally begins at the age of eighteen or nineteen, while old age is considered to begin at the age of legal retirement (approximately 65).

* Pre-conception: Ovum, Spermatozoon, Pre-existence
* Conception: Fertilization
* Pre-birth: Conception to birth
* Infancy: Birth to 2
* Childhood: 2 to 12
* Adolescence: 13 to 20
* Early Adulthood: 21 to 34
* Middle Adulthood: 35 to 54
* Late Adulthood: 55+
* Death
* Post-Death: Decomposition, Cryonics, (Afterlife, Ghost)

Ages can also be divided by decade:

* Denarian: someone between 10 and 19 years of age
* Vicenarian: someone between 20 and 29 years of age
* Tricenarian: someone between 30 and 39 years of age
* Quadragenarian: someone between 40 and 49 years of age
* Quinquagenarian: someone between 50 and 59 years of age
* Sexagenarian: someone between 60 and 69 years of age
* Septuagenarian: someone between 70 and 79 years of age
* Octogenarian: someone between 80 and 89 years of age
* Nonagenarian: someone between 90 and 99 years of age
* Centenarian: someone between 100 and 109 years of age
* Supercentenarian: someone over 110 years of age

[edit] Cognitive effects

Steady decline in many cognitive processes are seen across the lifespan, starting in one's thirties. Research has focused in particular on memory and aging, and has found decline in many types of memory with aging, but not in semantic memory or general knowledge such as vocabulary definitions, which typically increases or remains steady. Changes in cognition with age are discussed by Stuart-Hamilton (1994). As Stuart-Hamilton notes, early studies generally found declines in intelligence in the elderly, but may be criticised for being cross-sectional studies rather than longitudinal studies. Interestingly, evidence suggests that verbal intelligence may show a less sharp decline than other forms of intelligence. Creativity may also show a decline in age. While it is popularly believed that as people age, after around the age of thirty, intellectual skill will show a gradual decline, a rather different theory discussed by Stuart-Hamilton (1994) is the "terminal drop theory", which suggests that intellectual skills remain steady throughout life, and then plummet sharply as people near the end of their lives. Individual variations in rate of cognitive decline may, according to this theory, be explained in terms of people have different lengths of life.

[edit] Terminology

The concept of successful aging can be traced back to the 1950s, and popularised in the 1980s. Previous research into aging exaggerated the extent to which health disabilities, such as diabetes or osteoporosis, could be attributed exclusively to age, and research in gerontology exaggerated the homogeneity of samples of elderly people.[4][5]

Successful aging consists of three components:[6]

1. Low probability of disease or disability;
2. High cognitive and physical function capacity;
3. Active engagement with life.

A greater number of people self-report successful aging than those that strictly meet these criteria.[4]

Successful aging is viewed by Fentleman, Smith and Peterson(1990) as an interdisciplinary concept, spanning both psychology and sociology. They state that in the behavioural sciences, successful aging is to be understood as "a quality of the transaction between the changing person and the changing society over the entire life span, but especially during a person's later years" (Fentleman et alia, 1990; p50).

Healthy aging has been proposed as a more appropriate term.[4]

Optimal aging better takes into account how many elderly people suffer some health detriments, the cultural diversity in approaches to death and how, in Western Europe and Northern America, people may approach death may differ from approaches taken in other cultures.[7]

Vaillant (2002; cited in Aldwin & Gilmer, 2004) has listed six dimensions of optimal aging:

1. No physical disability over the age of 75 as rated by a physician; 2. Good subjective health assessment (i.e. good self-ratings of one's health); 3. Length of undisabled life; 4. Good mental health; 5. Objective social support; 6. Self-rated life satisfaction in eight domains, namely marriage, income-related work, children, friendship and social contacts, hobbies, community service activities, religion and recreation/ sports.

[edit] Theories

[[edit] Biological theories

Reproductive-Cell Cycle Theory
The idea that aging is regulated by reproductive hormones that act in an antagonistic pleiotrophic manner via cell cycle signaling, promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence (dyosis).
Wear-and-Tear theory
The idea that changes associated with aging are the result of chance damage that accumulates over time.
Somatic Mutation Theory
This is the biological theory that aging results from damage to the genetic integrity of the body’s cells.
Error Accumulation Theory
This is the idea that aging results from chance events that gradually damage the genetic code.
Accumulative-Waste Theory
The biological theory of aging that points to a buildup of cells of waste products that presumably interferes with metabolism.
Autoimmune Theory
This is the idea that aging results from gradual decline in the body’s immune system.
Aging-Clock Theory
The idea that aging results from a preprogrammed sequence, as in a clock, built into the operation of the nervous or endocrine system of the body.
Cross-Linkage Theory
This is the idea that aging results from accumulation of cross-linked compounds that interfere with normal cell function.
Free-Radical Theory
The idea that free radicals (unstable and highly reactive organic molecules, also named reactive oxygen species or oxidative stress) create damage that gives rise to symptoms we recognize as aging.
Mitohormesis
Recent evidence from Michael Ristow's laboratory suggests that a process called mitohormesis may prevent aging processes primarily caused by free radicals by increasing endogenous organismal resistance against reactive oxygen species and oxidative stress. [8]
Cellular Theory
This is the view that aging can be explained largely by changes in structure and function taking place in the cells of an organism.

[edit]

Charlie Rose introduces our course.

Please listen to this before the April 2 meeting.

COURSE OUTLINE

Course Outline

I. Introductions, *wikis , news in aging, How to define aging

II. Aging and Agism, What is aging (cont), comparative biology, embryology and the two ways to die.
*Wiki Slime Mold life cycle http://en.wikipedia.org/wiki/Dictyostelid
NEWS Aging and Death in E. coli http://evilutionarybiologist.blogspot.com/2007/08/even-bacteria-get-old.html


III. Genes and Telemeres
*Wiki Gene history http://en.wikipedia.org/wiki/Gene#History
NEWS Can aging be cured?http://www.huffingtonpost.com/dan-agin/methuselah-laughing-liar_b_74341.html


IV. Brain aging. Alzheimer’s disease and other dementias,
cholesterol.
*Wiki Hippocampus definition and role in memory. http://en.wikipedia.org/wiki/Hippocampus#Role_in_general_memory
News USC Gerontologists Set Longevity Record
http://blog.wired.com/wiredscience/2008/01/usc-gerontologi.html

V. Heart aging, cholesterol, antioxidants
*Wiki Mitochondria introduction http://en.wikipedia.org/wiki/Mitochondria

VI. Stem cells
wiki. Cellular senesence http://en.wikipedia.org/wiki/Senescence#Cellular_senescence
News Sirnaomics The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises
Paola Scaffidi, Leslie Gordon, Tom Misteli
News http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.

VII. Host defenses
wiki The immune system intro and layered defences http://en.wikipedia.org/wiki/
Immune_system
News
News Fighting Diseases Of Aging By Wasting Energy, Rather Than Dieting -- Works For Mice
http://www.sciencedaily.com/releases/2007/12/.htm

VIII. Future of aging research, Ethics
No wiki
News Reason as Our Guide
http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.
* A wiki is a brief description led by a class member on a topic found in the web site
,Wikipedia.

The unity of living cells: Week 2

Notice the similarity in the structure of all cells.